Overall - Project Summary/Abstract A surge in birth defects accompanied the arrival of Zika virus (ZIKV) in the Americas. As ZIKV spreads explosively in populations with no pre-existing immunity, an entire generation of pregnant women and their babies may be at risk for congenital Zika syndrome. Unfortunately, nearly nothing is known about the parameters impacting fetal risk during pregnancy?and epidemiological studies following large co- horts of pregnant women will take years. We developed the first nonhuman primate model for studying the impact of ZIKV infection during preg- nancy. The most provocative initial finding from these studies is that maternal viremia persists for weeks to months in pregnant macaques, in contrast to viremia that lasts only 7-10 days in non-pregnant ma- caques. The key hypothesis of this Program Project is that prolonged maternal viremia during pregnancy predicts fetal risk of congenital Zika syndrome. A corollary is that duration of sustained viremia can be used to assess the impact of co-factors and interventions that modulate the risk of con- genital Zika syndrome. We will explore this hypothesis through three integrated projects: Project 1. Define the impact of sustained ZIKV viremia in pregnancy on neonatal outcomes. We will assess the relationship among prolonged viremia, vertical transmission, and neonatal injury. Project 2. Assess whether pre-existing immunity to dengue virus, elicited by infection or vaccination with a licensed vaccine, increases the likelihood or duration of sustained ZIKV viremia in pregnancy. Project 3. Evaluate whether passive administration of ZIKV-specific antibodies can prevent acquisi- tion and/or reduce the severity of ZIKV when administered therapeutically. ZIKV is dangerous to pregnant women and their fetuses/neonates throughout the Americas. This risk will persist for at least several years, even if it is eventually curtailed by natural immunity and widespread vaccination. This Program Project will provide important new tools for pregnant women and their health- care providers to assess, and potentially reduce, the risk of congenital Zika syndrome.